The inflammatory milieu in injured and healing islets is a decisive factor in the development of autoimmune diabetes and yet we know very little about this milieu or how it contributes to immune regulation. We have recently identified a pivotal role for hyaluronan (HA), a component of the extracellular matrix (ECM) of injured and healing tissues, in the function and stability of Foxp3+ regulatory T-cells (Treg), a T-cell subset critical to the maintenance of immune tolerance. The effect of HA on Treg depends on its size. High molecular weight HA (HMW-HA), found in healing tissues, promotes Treg survival and function. HMW-HA does this by crosslinking CD44 and substituting for IL-2 in the IL-2R signaling required by Treg for their viability and for production of the key immunoregulatory cytokine IL-10. Consistent with this, CD44-/- mice have unremitting inflammation in response to injury, fewer Treg, and make less IL-10. HMW-HA therefore functions as a tissue integrity signal that supports Treg in healing tissues. Low-molecular weight HA (LMW-HA), characteristic of chronically inflamed tissues, inhibits Treg function and suppresses production of IL-10. LMW-HA is a Toll like receptor 2 (TLR2) ligand; LMW-HA may negatively regulate Treg function at sites of sterile inflammation in the same way that microbial TLR2 ligands are known to inhibit Treg at sites of active infection. Together, our data support a model whereby HA catabolism and signaling through CD44 and TLR2 link inflammation to Treg function at sites of sterile injury. If this model is correct, it may be possible to enhance Treg function, promote wound healing and prevent autoimmunity by supporting HA integrity. In vivo HA integrity is maintained by TSG-6 and other HA-binding molecules (hyaladherins) that covalently link HA strands. This prevents their degradation and promotes interactions with CD44. TSG-6 has been used experimentally to treat sepsis and other forms of inflammation but its value in autoimmunity is unknown. Here, we will elucidate the mechanisms by which HMW-HA and LMW-HA govern Treg behavior and determine what role HA integrity plays in Treg function in vivo using mouse models of autoimmune diabetes. The expected outcomes of these studies are a working knowledge of the mechanisms that govern immune regulation in injured and healing tissues and innovative, ECM-based strategies to promote wound healing and prevent autoimmunity. PUBLIC HEALTH RELEVANCE: The proposed studies will greatly advance our understanding of the mechanisms that govern immune regulation in injured and healing pancreatic islets and will open the doors to innovative strategies to prevent autoimmune diabetes.